Copper-catalysed dehydrogenation or lactonization of C(sp3)-H bonds.

Cytochrome P450 enzymes are known to catalyse bimodal oxidation of aliphatic acids via radical intermediates, which partition between pathways of hydroxylation and desaturation1,2. Developing analogous catalytic systems for remote C-H functionalization remains a significant challenge3-5. Here, we report the development of Cu(I)-catalysed bimodal dehydrogenation/lactonization reactions of synthetically common N-methoxyamides through radical abstractions of the γ-aliphatic C-H bonds. The feasibility of switching from dehydrogenation to lactonization is also demonstrated by altering reaction conditions. The use of a readily available amide as both radical precursor and internal oxidant allows for the development of redox-neutral C-H functionalization reactions with methanol as the sole side product. These C-H functionalization reactions using a Cu(I) catalyst with loading as low as 0.5 mol.% is applied to the diversification of a wide range of aliphatic acids including drug molecules and natural products. The exceptional compatibility of this catalytic system with a wide range of oxidatively sensitive functionality demonstrates the unique advantage of using a simple amide substrate as a mild internal oxidant.

Biocatalytic oxidative cross-coupling reactions for biaryl bond formation.

Biaryl compounds, with two connected aromatic rings, are found across medicine, materials science and asymmetric catalysis1,2. The necessity of joining arene building blocks to access these valuable compounds has inspired several approaches for biaryl bond formation and challenged chemists to develop increasingly concise and robust methods for this task3. Oxidative coupling of two C-H bonds offers an efficient strategy for the formation of a biaryl C-C bond; however, fundamental challenges remain in controlling the reactivity and selectivity for uniting a given pair of substrates4,5. Biocatalytic oxidative cross-coupling reactions have the potential to overcome limitations inherent to numerous small-molecule-mediated methods by providing a paradigm with catalyst-controlled selectivity6. Here we disclose a strategy for biocatalytic cross-coupling through oxidative C-C bond formation using cytochrome P450 enzymes. We demonstrate the ability to catalyse cross-coupling reactions on a panel of phenolic substrates using natural P450 catalysts. Moreover, we engineer a P450 to possess the desired reactivity, site selectivity and atroposelectivity by transforming a low-yielding, unselective reaction into a highly efficient and selective process. This streamlined method for constructing sterically hindered biaryl bonds provides a programmable platform for assembling molecules with catalyst-controlled reactivity and selectivity.

Lactonization as a general route to ß-C(sp3)-H functionalization.

Functionalization of the ß-C-H bonds of aliphatic acids is emerging as a valuable synthetic disconnection that complements a wide range of conjugate addition reactions1-5. Despite efforts for ß-C-H functionalization in carbon-carbon and carbon-heteroatom bond-forming reactions, these have numerous crucial limitations, especially for industrial-scale applications, including lack of mono-selectivity, use of expensive oxidants and limited scope6-13. Notably, the majority of these reactions are incompatible with free aliphatic acids without exogenous directing groups. Considering the challenge of developing C-H activation reactions, it is not surprising that achieving different transformations requires independent catalyst design and directing group optimizations in each case. Here we report a Pd-catalysed ß-C(sp3)-H lactonization of aliphatic acids enabled by a mono-N-protected ß-amino acid ligand. The highly strained and reactive ß-lactone products are versatile linchpins for the mono-selective installation of diverse alkyl, alkenyl, aryl, alkynyl, fluoro, hydroxyl and amino groups at the ß position of the parent acid, thus providing a route to many carboxylic acids. The use of inexpensive tert-butyl hydrogen peroxide as the oxidant to promote the desired selective reductive elimination from the Pd(IV) centre, as well as the ease of product purification without column chromatography, render this reaction amenable to tonne-scale manufacturing.

Biosynthesis of tetrahydropapaverine and semisynthesis of papaverine in yeast.

Tetrahydropapaverine (THP) and papaverine are plant natural products with clinically significant roles. THP is a precursor in the production of the drugs atracurium and cisatracurium, and papaverine is used as an antispasmodic during vascular surgery. In recent years, metabolic engineering advances have enabled the production of natural products through heterologous expression of pathway enzymes in yeast. Heterologous biosynthesis of THP and papaverine could play a role in ensuring a stable supply of these clinically significant products. Biosynthesis of THP and papaverine has not been achieved to date, in part because multiple pathway enzymes have not been elucidated. Here, we describe the development of an engineered yeast strain for de novo biosynthesis of THP. The production of THP is achieved through heterologous expression of two enzyme variants with activity on nonnative substrates. Through protein engineering, we developed a variant of N-methylcoclaurine hydroxylase with activity on coclaurine, enabling de novo norreticuline biosynthesis. Similarly, we developed a variant of scoulerine 9-O-methyltransferase capable of O-methylating 1-benzylisoquinoline alkaloids at the 3' position, enabling de novo THP biosynthesis. Flux through the heterologous pathway was improved by knocking out yeast multidrug resistance transporters and optimization of media conditions. Overall, strain engineering increased the concentration of biosynthesized THP 600-fold to 121 µg/L. Finally, we demonstrate a strategy for papaverine semisynthesis using hydrogen peroxide as an oxidizing agent. Through optimizing pH, temperature, reaction time, and oxidizing agent concentration, we demonstrated the ability to produce semisynthesized papaverine through oxidation of biosynthesized THP.

Structural insights into the action mechanisms of artificial electron acceptors in photosystem II.

Photosystem II (PSII) utilizes light energy to split water, and the electrons extracted from water are transferred to QB, a plastoquinone molecule bound to the D1 subunit of PSII. Many artificial electron acceptors (AEAs) with molecular structures similar to that of plastoquinone can accept electrons from PSII. However, the molecular mechanism by which AEAs act on PSII is unclear. Here, we solved the crystal structure of PSII treated with three different AEAs, 2,5-dibromo-1,4-benzoquinone, 2,6-dichloro-1,4-benzoquinone, and 2-phenyl-1,4-benzoquinone, at 1.95 to 2.10 Å resolution. Our results show that all AEAs substitute for QB and are bound to the QB-binding site (QB site) to receive electrons, but their binding strengths are different, resulting in differences in their efficiencies to accept electrons. The acceptor 2-phenyl-1,4-benzoquinone binds most weakly to the QB site and showed the highest oxygen-evolving activity, implying a reverse relationship between the binding strength and oxygen-evolving activity. In addition, a novel quinone-binding site, designated the QD site, was discovered, which is located in the vicinity of QB site and close to QC site, a binding site reported previously. This QD site is expected to play a role as a channel or a storage site for quinones to be transported to the QB site. These results provide the structural basis for elucidating the actions of AEAs and exchange mechanism of QB in PSII and also provide information for the design of more efficient electron acceptors.

Dioxygen Reduction and Bioinspired Oxidations by Non-heme Iron(II)-α-Hydroxy Acid Complexes.

ConspectusAerobic organisms involve dioxygen-activating iron enzymes to perform various metabolically relevant chemical transformations. Among these enzymes, mononuclear non-heme iron enzymes reductively activate dioxygen to catalyze diverse biological oxidations, including oxygenation of C-H and C═C bonds and C-C bond cleavage with amazing selectivity. Several non-heme enzymes utilize organic cofactors as electron sources for dioxygen reduction, leading to the generation of iron-oxygen intermediates that act as active oxidants in the catalytic cycle. These unique enzymatic reactions influence the design of small molecule synthetic compounds to emulate enzyme functions and to develop bioinspired catalysts for performing selective oxidation of organic substrates with dioxygen. Selective electron transfer during dioxygen reduction on iron centers of synthetic models by a sacrificial reductant requires appropriate design strategies. Taking lessons from the role of enzyme-cofactor complexes in the selective electron transfer process, our group utilized ternary iron(II)-α-hydroxy acid complexes supported by polydentate ligands for dioxygen reduction and bioinspired oxidations. This Account focuses on the role of coordinated sacrificial reductants in the selective electron transfer for dioxygen reduction by iron complexes and highlights the versatility of iron(II)-α-hydroxy acid complexes in affecting dioxygen-dependent oxidation/oxygenation reactions. The iron(II)-coordinated α-hydroxy acid anions undergo two-electron oxidative decarboxylation concomitant with the generation of reactive iron-oxygen oxidants. A nucleophilic iron(II)-hydroperoxo species was intercepted in the decarboxylation pathway. In the presence of a Lewis acid, the O-O bond of the nucleophilic oxidant is heterolytically cleaved to generate an electrophilic iron(IV)-oxo-hydroxo oxidant. Most importantly, the oxidants generated with or without Lewis acid can carry out cis-dihydroxylation of alkenes. Furthermore, the electrophilic iron-oxygen oxidant selectively hydroxylates strong C-H bonds. Another electrophilic iron(IV)-oxo oxidant, generated from the iron(II)-α-hydroxy acid complexes in the presence of a protic acid, carries out C-H bond halogenation by using a halide anion.Thus, different metal-oxygen intermediates could be generated from dioxygen using a single reductant, and the reactivity of the ternary complexes can be tuned using external additives (Lewis/protic acid). The catalytic potential of the iron(II)-α-hydroxy complexes in performing O2-dependent oxygenations has been demonstrated. Different factors that govern the reactivity of iron-oxygen oxidants from ternary iron(II) complexes are presented. The versatile reactivity of the oxidants provides useful insights into developing catalytic methods for the selective incorporation of oxidized functionalities under environmentally benign conditions using aerial oxygen as the terminal oxidant.

Origins of Selective Oxidation in Carbon-Based Nonradical Oxidation Processes toward Organic Pollutants: Quantitative Structure-Activity Relationships (QSARs).

Metal-free carbon material-mediated nonradical oxidation processes (C-NOPs) have emerged as a research hotspot due to their excellent performance in selectively eliminating organic pollutants in aqueous environments. However, the selective oxidation mechanisms of C-NOPs remain obscure due to the diversity of organic pollutants and nonradical active species. Herein, quantitative structure-activity relationship (QSAR) models were employed to unveil the origins of C-NOP selectivity toward organic pollutants in different oxidant systems. QSAR analysis based on adsorption and oxidation descriptors revealed that C-NOP selectivity depends on the oxidation potentials of organic pollutants rather than on adsorption interactions. However, the dominance of electronic effects in selective oxidation decreases with increasing structural complexity of organic pollutants. Moreover, the oxidation threshold solely depends on the inherent electronic nature of organic pollutants and not on the reactivity of nonradical active species. Notably, the accuracy of substituent descriptors (Hammett constants) and theoretical descriptors (e.g., highest occupied molecular orbital energy, ionization potential, and single-electron oxidation potential) is significantly influenced by the complexity and molecular state of organic pollutants. Overall, the study findings reveal the origins of organic pollutant-oriented selective oxidation and provide insight into the application of descriptors in QSAR analysis.

From Theory to Practice: Leveraging Chemical Principles To Improve the Performance of Peroxydisulfate-Based In Situ Chemical Oxidation of Organic Contaminants.

In situ chemical oxidation (ISCO) using peroxydisulfate has become more popular in the remediation of soils and shallow groundwater contaminated with organic chemicals. Researchers have studied the chemistry of peroxydisulfate and the oxidative species produced upon its decomposition (i.e., sulfate radical and hydroxyl radical) for over five decades, describing reaction kinetics, mechanisms, and product formation in great detail. However, if this information is to be useful to practitioners seeking to optimize the use of peroxydisulfate in the remediation of hazardous waste sites, the relevant conditions of high oxidant concentrations and the presence of minerals and solutes that affect radical chain reactions must be considered. The objectives of this Review are to provide insights into the chemistry of peroxydisulfate-based ISCO that can enable more efficient operation of these systems and to identify research needed to improve understanding of system performance. By gaining a deeper understanding of the underlying chemistry of these complex systems, it may be possible to improve the design and operation of peroxydisulfate-based ISCO remediation systems.

An improved process for removal and recovery of heavy petroleum from solids using a ferrate-based hybrid oxidant.

Persulfate oxidants are widely used in soil remediation and wastewater treatment but perform poorly in degrading polycyclic aromatic hydrocarbons (PAHs), especially heavy fractions in solids. Herein, we propose the utilization of a green peroxymonosulfate-ferrate-FeS (PFI) oxidant as a promising process aid for remediating soils contaminated with heavy petroleum components, including asphaltenes and resins. The PFI oxidant could degrade heavy petroleum fractions because of dual activation of the peroxymonosulfate and ferrate by FeS at ambient conditions. Nevertheless, when dealing with soil with high oil content (>10%), the degradation efficiency remains limited (<30%) regardless of the quantity of oxidants employed. Surface elemental analysis shows that a coating of secondary products (Fe(OH)3, Fe2O3) on the surface and in pores of the soil-pollutant matrix explains the failure of oxidation and inefficient use of oxidant. To address this issue, a strategy of pre-solvent extraction-oxidation hybrid process with sequent acidic washing is proposed, where dichloromethane serves as the solvent, and PFI acts as the oxidant. In this system over 90% of the oil could be recovered with an oxidation efficiency of 80% by alleviating the problem of iron oxide coating the matrix surface. The oxidant consumption is also reduced to 70 wt% of the sludge. The PFI oxidant is found to exhibit excellent universality in treating oily sludge with low petroleum content (<2%), reducing the petroleum content in the residue to less than 0.3 wt% (meeting the national standards). The degradation of low oil content sludge by the PFI oxidant followed pseudo first-order kinetics. These findings not only elucidate the failure of PFI oxidation for high oil content oily sludge and identify its potential engineering application range, but also offer a practical strategy for processing petroleum-contaminated soil with varying oil contents through wet oxidation.

Redox Properties of Bacillus subtilis Ferredoxin:NADP+ Oxidoreductase: Potentiometric Characteristics and Reactions with Pro-Oxidant Xenobiotics.

Bacillus subtilis ferredoxin:NADP+ oxidoreductase (BsFNR) is a thioredoxin reductase-type FNR whose redox properties and reactivity with nonphysiological electron acceptors have been scarcely characterized. On the basis of redox reactions with 3-acetylpyridine adenine dinucleotide phosphate, the two-electron reduction midpoint potential of the flavin adenine dinucleotide (FAD) cofactor was estimated to be -0.240 V. Photoreduction using 5-deazaflavin mononucleotide (5-deazaFMN) as a photosensitizer revealed that the difference in the redox potentials between the first and second single-electron transfer steps was 0.024 V. We examined the mechanisms of the reduction of several different groups of non-physiological electron acceptors catalyzed by BsFNR. The reactivity of quinones and aromatic N-oxides toward BsFNR increased when increasing their single-electron reduction midpoint redox potentials. The reactivity of nitroaromatic compounds was lower due to their lower electron self-exchange rate, but it exhibited the same trend. A mixed single- and two-electron reduction reaction was characteristic of quinones, whereas reactions involving nitroaromatics proceeded exclusively via the one-electron reduction reaction. The oxidation of FADH• to FAD is the rate-limiting step during the oxidation of fully reduced FAD. The calculated electron transfer distances in the reaction with nitroaromatics were close to those of other FNRs including the plant-type enzymes, thus demonstrating their similar active site accessibility to low-molecular-weight oxidants despite the fundamental differences in their structures.

Degradation of triclosan by peroxydisulfate/peroxomonosulfate binary oxidants activation under thermal conditions: Efficiency and mechanism.

Peroxydisulfate (PDS) and peroxymonosulfate (PMS) could be efficiently activated by heat to generate reactive oxygen species (ROS) for the degradation of organic contaminants. However, defects including the inefficiency treatment and pH dependence of monooxidant process are prominent. In this study, synergy of heat and the PDS-PMS binary oxidant was studied for efficient triclosan (TCS) degradation and apply in rubber wastewater. Under different pH values, the degradation of TCS followed pseudo-first-order kinetics, the reaction rate constant (kobs) value of TCS in heat/PDS/PMS system increased from 1.8 to 4.4 fold and 6.8-49.1 fold when compared to heat/PDS system and heat/PMS system, respectively. Hydroxyl radicals (·OH), sulfate radicals (SO4·-) and singlet oxygen (1O2) were the major ROS for the degradation of TCS in heat/PDS/PMS system. In addition, the steady-state concentrations of ·OH/1O2 and SO4·-/·OH/1O2 increased under acidic conditions and alkaline conditions, respectively. It was concluded that the pH regulated the ROS for degradation of TCS in heat/PDS/PMS system significantly. Based on the analysis of degradation byproducts, it was inferred that the dechlorination, hydroxylation and ether bond breaking reactions occurred during the degradation of TCS. Moreover, the biological toxicity of the ten byproducts was lower than that of TCS was determined. Furthermore, the heat/PDS/PMS system is resistant to the influence of water substrates and can effectively improve the water quality of rubber wastewater. This study provides a novel perspective for efficient degradation of TCS independent of pH in the heat/PDS/PMS system and its application of rubber wastewater.

Using CO2 and oxidants for in situ regeneration of permeable reactive barriers for leachate-contaminated groundwater.

Groundwater contamination near landfills is commonly caused by leachate leakage, and permeable reactive barriers (PRBs) are widely used for groundwater remediation. However, the deactivation and blockage of the reactive medium in PRBs limit their long-term effectiveness. In the current study, a new methodology was proposed for the in situ regeneration of PRB to remediate leachate-contaminated groundwater. CO2 coupled with oxidants was applied for the dispersion and regeneration of the fillers; by injecting CO2 to disperse the fillers, the permeability of the PRB was increased and the oxidants could flow evenly into the PRB. The results indicate that the optimum filler proportion was zero-valent iron (ZVI)/zeolites/activated carbon (AC) = 3:8:10 and the optimum oxidant proportion was COD/Na2S2O8/H2O2/Fe2+ = 1:5:6:5; the oxidation system of Fe2+/H2O2/S2O82- has a high oxidation efficiency and persistence. The average regeneration rate of zeolites was 72.71%, and the average regeneration rate of AC was 68.40%; the permeability of PRB also increased. This technology is effective for the remediation of landfills in China that have large contaminated areas, an uneven pollutant concentration distribution, and a long pollution duration. The purification mode of long-term adsorption and short-time in situ oxidation can be applied to the remediation of long-term high-concentration organically polluted groundwater, where pollution sources are difficult to cut off.

Substrate Conformation Regulates Aromatic C-H Vs C-F Bond Activation in Heme-Dependent Tyrosine Hydroxylase.

A recently discovered heme-dependent enzyme tyrosine hydroxylase (TyrH) offers a green approach for functionalizing the high-strength C-H and C-F bonds in aromatic compounds. However, there is ambiguity regarding the nature of the oxidant (compound 0 or compound I) involved in activating these bonds. Herein, using comprehensive molecular dynamics (MD) simulations and hybrid quantum mechanical/molecular mechanical calculations, we reveal that it is compound I (Cpd I) that acts as the primary oxidant involved in the functionalization of both C-F and C-H bonds. The energy barrier for C-H and C-F activation using compound 0 (Cpd 0) as an oxidant was very high, indicating that Cpd 0 cannot be an oxidant. Consistent with the previous experimental finding, our simulation shows two different conformations of the substrate, where one orientation favors the C-H activation, while the other conformation prefers the C-F activation. As such, our mechanistic study shows that nature utilizes just one oxidant, that is, Cpd I, but it is the active site conformation that decides whether it selects C-F or C-H functionalization which may resemble involvement of two different oxidants.

Oxidation of Organic Compounds Using Water as the Oxidant with H2 Liberation Catalyzed by Molecular Metal Complexes.

Oxidation reactions of organic compounds play a central role in both industrial chemical and material synthesis as well as in fine chemical and pharmaceutical synthesis. While traditional laboratory-scale oxidative syntheses have relied on the use of strong oxidizers, modern large-scale oxidation processes preferentially utilize air or pure O2 as an oxidant, with other oxidants such as hydrogen peroxide, nitric acid, and aqueous chlorine solution also being used in some processes. The use of molecular oxygen or air as an oxidant has been very attractive in recent decades because of the abundance of air and the lack of wasteful byproduct generation. Nevertheless, the use of high-pressure air or, in particular, pure oxygen can lead to serious safety concerns with improper handling and also necessitates the use of sophisticated high-pressure reactors for the processes.Several research groups, including ours, have investigated in recent times the possibility of carrying out catalytic oxidation reactions using water as the formal oxidant, with no added conventional oxidants. Along with the abundant availability of water, these processes also generate dihydrogen gas as the reaction coproduct, which is a highly valuable fuel. Several well-defined molecular metal complexes have been reported in recent years to catalyze these unusual oxidative reactions with water. A ruthenium bipyridine-based PNN pincer complex was reported by us to catalyze the oxidation of primary alcohols to carboxylate salts with alkaline water along with H2 liberation, followed by reports by other groups using other complexes as catalysts. At the same time, ruthenium-, iridium-, and rhodium-based complexes have been reported to catalyze aldehyde oxidation to carboxylic acids using water. Our group has combined the catalytic aqueous alcohol and aldehyde oxidation activity of a ruthenium complex to achieve the oxidation of biomass-derived renewable aldehydes such as furfural and 5-hydroxymethylfurfural (HMF) to furoic acid and furandicarboxylic acid (FDCA), respectively, using alkaline water as the oxidant, liberating H2. Ruthenium complexes with an acridine-based PNP ligand have also been employed by our group for the catalytic oxidation of amines to the corresponding lactams, or to carboxylic acids via a deaminative route, using water. Similarly, we also reported molecular complexes for the catalytic Markovnikov oxidation of alkenes to ketones using water, similar to Wacker-type oxidation, which, however, does not require any terminal oxidant and produces H2 as the coproduct. At the same time, the oxidation of enol ethers to the corresponding esters with water has also been reported. This account will highlight these recent advances where water was used as an oxidant to carry out selective oxidation reactions of organic compounds, catalyzed by well-defined molecular complexes, with H2 liberation. The oxidation of alcohols, aldehydes, amines, alkenes, and enol ethers will be discussed to provide an outlook toward other functional groups' oxidation. We hope that this will aid researchers in devising other oxidative dehydrogenative catalytic systems using water, complementing traditional oxidative processes involving strong oxidants and molecular oxygen.

Selective Hydroxylation of C(sp3 )-H Bonds in Steroids.

Steroids are highly prevalent structures in small-molecule therapeutics, with the level of oxidation being key to their biological activity and physicochemical properties. These C(sp3 )-rich tetracycles contain many stereocentres, which are important for creating specific vectors and protein binding orientations. Therefore, the ability to hydroxylate steroids with a high degree of regio-, chemo- and stereoselectivity is essential for researchers working in this field. This review will cover three main methods for the hydroxylation of steroidal C(sp3 )-H bonds: biocatalysis, metal-catalysed C-H hydroxylation and organic oxidants, such as dioxiranes and oxaziridines.

Reaction of Amino Acids with Ferrate(VI): Impact of the Carboxylic Group on the Primary Amine Oxidation Kinetics and Mechanism.

Ferrate (Fe(VI)) is a novel oxidant that can be used to mitigate disinfection byproduct (DBP) precursors. However, the reaction of Fe(VI) with organic nitrogen, which is a potential precursor of potent nitrogenous DBPs, remains largely unexplored. The present work aimed to identify the kinetics and products for the reaction of Fe(VI) with primary amines, notably amino acids. A new kinetic model involving ionizable intermediates was proposed and can describe the unusual pH effect on the Fe(VI) reactivity toward primary amines and amino acids. The Fe(VI) oxidation of phenylalanine produced a mixture of nitrile, nitrite/nitrate, amide, and ammonia, while nitroalkane was an additional product in the case of glycine. The product distribution for amino acids significantly differed from that of uncarboxylated primary amines that mainly generate nitriles. A general reaction pathway for primary amines and amino acids was proposed and notably involved the formation of imines, the degradation of which was affected by the presence of a carboxylic group. In comparison, ozonation led to higher yields of nitroalkanes that could be readily converted to potent halonitroalkanes during chlor(am)ination. Based on this study, Fe(VI) can effectively mitigate primary amine-based, nitrogenous DBP precursors with little formation of toxic halonitroalkanes.

Methylmercury Degradation by Trivalent Manganese.

Methylmercury (MeHg) is a potent neurotoxin and has great adverse health impacts on humans. Organisms and sunlight-mediated demethylation are well-known detoxification pathways of MeHg, yet whether abiotic environmental components contribute to MeHg degradation remains poorly known. Here, we report that MeHg can be degraded by trivalent manganese (Mn(III)), a naturally occurring and widespread oxidant. We found that 28 ± 4% MeHg could be degraded by Mn(III) located on synthesized Mn dioxide (MnO2-x) surfaces during the reaction of 0.91 µg·L-1 MeHg and 5 g·L-1 mineral at an initial pH of 6.0 for 12 h in 10 mM NaNO3 at 25 °C. The presence of low-molecular-weight organic acids (e.g., oxalate and citrate) substantially enhances MeHg degradation by MnO2-x via the formation of soluble Mn(III)-ligand complexes, leading to the cleavage of the carbon-Hg bond. MeHg can also be degraded by reactions with Mn(III)-pyrophosphate complexes, with apparent degradation rate constants comparable to those by biotic and photolytic degradation. Thiol ligands (cysteine and glutathione) show negligible effects on MeHg demethylation by Mn(III). This research demonstrates potential roles of Mn(III) in degrading MeHg in natural environments, which may be further explored for remediating heavily polluted soils and engineered systems containing MeHg.

In-crystal reaction cycle of a toluene-bound diiron hydroxylase.

Electrophilic aromatic substitution is one of the most important and recognizable classes of organic chemical transformation. Enzymes create the strong electrophiles that are needed for these highly energetic reactions by using O2, electrons, and metals or other cofactors. Although the nature of the oxidants that carry out electrophilic aromatic substitution has been deduced from many approaches, it has been difficult to determine their structures. Here we show the structure of a diiron hydroxylase intermediate formed during a reaction with toluene. Density functional theory geometry optimizations of an active site model reveal that the intermediate is an arylperoxo Fe2+/Fe3+ species with delocalized aryl radical character. The structure suggests that a carboxylate ligand of the diiron centre may trigger homolytic cleavage of the O-O bond by transferring a proton from a metal-bound water. Our work provides the spatial and electronic constraints needed to propose a comprehensive mechanism for diiron enzyme arene hydroxylation that accounts for many prior experimental results.

Modifying the resolving cysteine affects the structure and hydrogen peroxide reactivity of peroxiredoxin 2.

Peroxiredoxin 2 (Prdx2) is a thiol peroxidase with an active site Cys (C52) that reacts rapidly with H2O2 and other peroxides. The sulfenic acid product condenses with the resolving Cys (C172) to form a disulfide which is recycled by thioredoxin or GSH via mixed disulfide intermediates or undergoes hyperoxidation to the sulfinic acid. C172 lies near the C terminus, outside the active site. It is not established whether structural changes in this region, such as mixed disulfide formation, affect H2O2 reactivity. To investigate, we designed mutants to cause minimal (C172S) or substantial (C172D and C172W) structural disruption. Stopped flow kinetics and mass spectrometry showed that mutation to Ser had minimal effect on rates of oxidation and hyperoxidation, whereas Asp and Trp decreased both by ∼100-fold. To relate to structural changes, we solved the crystal structures of reduced WT and C172S Prdx2. The WT structure is highly similar to that of the published hyperoxidized form. C172S is closely related but more flexible and as demonstrated by size exclusion chromatography and analytical ultracentrifugation, a weaker decamer. Size exclusion chromatography and analytical ultracentrifugation showed that the C172D and C172W mutants are also weaker decamers than WT, and small-angle X-ray scattering analysis indicated greater flexibility with partially unstructured regions consistent with C-terminal unfolding. We propose that these structural changes around C172 negatively impact the active site geometry to decrease reactivity with H2O2. This is relevant for Prdx turnover as intermediate mixed disulfides with C172 would also be disruptive and could potentially react with peroxides before resolution is complete.

Light-Initiated C-H Activation via Net Hydrogen Atom Transfer to a Molybdenum(VI) Dioxo.

MoO2Cl2(bpy-tBu) (1) is shown to be a potent one-electron oxidant upon irradiation with 365 nm light in various solvents, while being a weak two-electron oxidant in the dark. Complex 1 is characterized to activate various types of C-H bonds photochemically, including allylic and benzylic positions as well as alkanes and aldehydes. In all of these oxidations, 1 ultimately forms a bimetallic Mo(V)/Mo(V) species with a µ-oxo ligand (2). Depending on the substrate, the major organic product is identified as either an oxygenated or a C-C coupled (homodimerized) compound along with a minor chlorinated species. The product selectivity is proposed to be dependent upon the relative values between the bond dissociation enthalpy (BDE) of a potentially new C-OH bond within the product versus the BDE of a Mo-OH motif within a Mo(V)O(OH) intermediate. Based on this, we can estimate the BDE for Mo-OH to be 83-93 kcal/mol. Mechanistic studies suggest that the C-H activation occurs via a net hydrogen atom transfer (HAT) from 1* occurring either asynchronously or via a stepwise electron-proton transfer (ET-PT) process. Complex 2 is further demonstrated to reform dioxo 1 in the presence of chemical oxidants.